Telomerase plays a crucial role in cellular immortality and is expressed in most tumor cells as well as stem cells and germ lines. Mutations in several telomerase genes, e.g. telomerase reverse transcriptase (TERT), have been genetically linked to human diseases such as dyskeratosis congenita (DKC) and aplastic anemia (AA) that have symptoms of bone marrow failure. The biological consequences of telomerase deficiency have been studied mostly using cultured human cells or mice as an animal model. Teleost fish, such as zebrafish and medaka fish, have emerged as powerful genetic model systems in the past few decades. They are attractive vertebrate models for biomedical research because of their small size and large numbers of progeny per generation. We have successfully generated a mutant medaka fish that contains a nonsense mutation TERTK195X in the medaka TERT gene. This is the first telomerase-deficient fish model ever created. The overall goal of this proposed program is to develop and use the medaka fish model for the study of telomeres and telomerase, and their role in DKC and tumorigenesis. The first specific aim of this project will focus on characterization of telomere length phenotype and germ cell defect of the TERTK195X mutant medaka fish. The second specific aim will focus on the role of telomerase deficiency and telomere dysfunction in hematopoiesis and tumorigenesis. PUBLIC HEALTH RELEVANCE: Telomerase is an enzyme crucial for cellular immortality and play critical roles in cancer, aging and several human diseases including dyskeratosis congenita, aplastic anemia and idiopathic pulmonary fibrosis. By generating a mutant fish that lacks telomerase enzyme, we will develop a powerful fish model system for studying the biological roles of telomerase and telomeres in cells, and finding potential cures for cancer and telomerase-dysfunction diseases.